Primary lateral sclerosis (PLS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are related disorders that are thought to represent different phenotypes on the same spectrum of neurodegenerative disorders. Pathological studies have shown common misfolded proteins in neuronal inclusions in brains of ALS and a subset of FTD patients, including in ALSFTD caused by an expansion mutation in the gene C9ORF72 that has been found to account for a significant portion of familial ALS and FTD in the United States. A recent hypothesis is that degeneration can be transmitted through axonal tracts or by local spread of misfolded proteins. If true, PLS may represent an exceptional condition in which the degenerative process fails to spread to a significant extent beyond the motor cortex. Understanding factors that limit spread in PLS patients may provide clues to mechanisms for halting progression of degeneration. The first aim of this project is to understand the relationship between disorders on the motor neuron disease spectrum. During FY14, we completed and published two studies of phenotypic characteristics of PLS and sporadic ALS patients. In a chart review analysis of the pattern of symptom spread in our longitudinal cohort of PLS patients, we found evidence for both axonal and contiguous spread of degeneration. A chart review also revealed that PLS patients had a higher incidence of pseudobulbar affect (PBA) than sporadic ALS patients. Regardless of ALS or PLS diagnosis, PBA was associated with alterations in diffusion tensor imaging properties of axonal pathways in the cortico-ponto-cerebellar circuit, consistent with the proposal that PBA can be viewed as a dysmetria of emotional expression. Additionally, work continued in the past year to compare diffusion tensor imaging measures between FTD, ALS, PLS and corticobasal syndrome patients in collaboration with the former Cognitive Neuroscience section. A second aim of the project is to identify reliable, preferably non-invasive markers for detection and measuring progression, particularly subclinical progression, in motor neuron disorders. We began a major new project in FY14 to prospectively document the natural history of C9ORF72- related familial ALS-FTD. In this collaborative project with the National Institute of Aging and investigators at the Johns Hopkins University, we are examining proposed biomarkers in symptomatic patients and presymptomatic carriers. One goal is to identify biomarkers that may provide an early signal of response in future clinical trials. Our research unit is coordinating the clinical component of this study and assessing imaging and physiological biomarkers. The multimodal imaging battery includes resting-state functional MRI, diffusion tensor imaging, and high resolution T1 imaging. Physiological candidate biomarkers include transcranial magnetic stimulation, electroimpedance myography, and the motor unit number index measure. Collaborating investigators are assessing spinal fluid, plasma, and cell-derived markers. Fourteen participants were enrolled in FY14. We have also carried out the same multimodal imaging battery on a cohort of 20 healthy controls for 2 sessions to determine the repeatability of imaging markers. In addition to the two primary aims of this project, we continued participation in two collaborative studies in FY14. We continued as a site in a collaborative study to examine the role of oxidative stress in progression of motor neuron diseases organized by Columbia University. We will complete the 3-year follow-up on all patients from our site.in early 2015. Columbia University has carried out a preliminary analysis of the baseline characteristics of the 41 PLS patients, including exome sequencing, and the manuscript is in draft. The collaboration with the NINDS Section on Infections of the Nervous System to look for evidence of endogenous retroviruses did not find transcriptase activity in the serum of 30 PLS patients, and analysis for viral sequences continues.